PROJECT ABSTRACT Obsessive-compulsive disorder (OCD), which is characterized by intrusive thoughts and repetitive behaviors, is a debilitating mental disorder that affects ~2% of adults in the United States. Although little is known of the cause and pathology of the disease, numerous human imaging studies have found that the orbitofrontal cortex (OFC) and striatum are hyperactive in patients with OCD. In accordance with these findings, recent work from our lab has shown that chronic optogenetic stimulation of medial OFC (mOFC) axon terminals in the ventromedial striatum (VMS) induces repetitive grooming that progressively increases over several days of stimulation. Moreover, grooming is not time-locked to stimulation and persists for up to 2 weeks after stimulation cessation, suggesting that plasticity within the OFC-striatal circuit underlies this behavior. Providing further evidence of plasticity, in vivo electrophysiological recordings demonstrate that the striatal evoked firing rate increases over the course of chronic stimulation. Within the striatum, dopamine type 1 receptor-expressing medium spiny neurons (D1-MSNs) are an excellent candidate for the mechanism of this perseverative grooming. Treatment with SKF compounds, including both partial and full D1 agonists, robustly increases abnormal grooming behavior, while global deletion of D1 receptors prevents SKF-induced grooming. Moreover, preliminary in vivo microendoscopy work from our lab indicates that D1-MSN calcium activity is specifically elevated during abnormal grooming behavior in SAPAP3 knockout mice, a model that exhibits an OCD-like compulsive grooming phenotype. We therefore hypothesize that D1-MSNs underlie the induction of perseverative grooming behavior in our optogenetic system. To test this hypothesis, we will use a combination of techniques that will elucidate the neural basis of perseverative grooming: slice electrophysiology, optogenetic stimulation paired with cell-type specific inhibition, and activity-dependent ensemble characterization. Through these experiments, we predict that: 1) there will be a selective potentiation of D1-MSN corticostriatal synapses after chronic mOFC-VMS stimulation, 2) D1-MSN inhibition will attenuate the induction of perseverative grooming, and 3) perseverative grooming ensembles will contain an increased proportion of D1-MSNs. The proposed aims will examine the cell-type specific changes in mOFC-VMS signaling that underlie the expression of perseverative grooming. These experiments will elucidate the mechanisms of dysfunctional corticostriatal signaling, which is necessary to advance our understanding of OCD pathology and treatment. In addition, detailed analysis of the role of D1-MSNs in perseverative behavior could reveal a viable therapeutic target for human trials. Finally, this research plan will allow me to fulfill my training goals of learning techniques for ex vivo electrophysiology and activity-dependent labeling of neural ensembles, which will facilitate my long-term goal of dissecting compulsive behavioral disorders as an independent investigator.